The oscillating mystery: The effects of forty-hertz entrainment in treating Alzheimer's disease

Imagine standing at crossroads unable to find your way home or gazing into the eyes of your loved one without remembering their name. For some, this is not merely imagination but the reality of Alzheimer's disease (AD). AD is a neurodegenerative disease that predominantly affects the elderly and stands as the leading cause of dementia. However, its etiology and pathogenesis remain poorly understood. One hallmark of AD is the accumulation of abnormal proteins in the brain, including amyloid-beta (Aβ) and tau. These proteins can disrupt the normal functioning of neurons and lead to their eventual death.

Since 2016, a series of studies¹ have demonstrated that 40-Hz stimulation effectively improves the cognitive abilities of AD model mice. This improvement is attributed to the reduction of accumulated amyloid-β (Aβ) proteins and the enhancement of microglial function, both of which are associated with the disease. However, these findings have been challenged by recent research² conducted by Prof. Buzsáki and published in Nature Neuroscience. In this study, the research team utilized two AD mouse models, specifically APP/PS1 and 5xFAD, to explore the effects of both acute and chronic 40-Hz light stimulation on Aβ, microglia, and gamma oscillations. Firstly, they discovered that 40-Hz light stimulation had no effect on the level of Aβ deposition or the morphology of microglia, whether tested in vitro or in vivo. Subsequently, they demonstrated that the entrainment does not activate native gamma oscillations in the targeted brain regions (visual cortex, hippocampus, and entorhinal cortex). Furthermore, they observed that 40-Hz light stimulation induced aversion and avoidance behavior in mice. This was evident from the duration the mice spent in the compartment with 40-Hz light compared to the one with continuous light. Given the absence of experiments assessing cognitive functions before and after 40-Hz entrainment, the observed inconsistencies in pathological changes in AD following acute or chronic exposure should be considered with caution. For example, the inability to replicate the beneficial effects of flickering light stimulation on Aβ and microglia may be attributed to variations in the experimental parameters. Although both animal models and human subjects have shown improvements in cognitive functions (such as memory) after 40-Hz entrainment, the underlying mechanisms driving these changes remain elusive. Nevertheless, this study successfully eliminated one potential mechanism for reducing AD symptoms—namely, the entrainment of natural gamma-band oscillations. The search for alternative mechanisms continues.

Given the notable behavioral improvement resulting from 40-Hz stimulation, it is indisputable that the underlying mechanism must have a significant association with gamma-band activity (30–100 Hz). The broad frequency band comprises multiple sub-gamma oscillations, each playing distinct roles. Another study³ from Prof. Buzsáki's laboratory provides direct evidence of the role of distinct gamma rhythms in cognitive function, specifically focusing on learning. During the spatial learning process, high-frequency gamma oscillations were found to synchronize the medial entorhinal cortex (MEC) and dentate gyrus (DG), thereby entraining the granule cells. Conversely, low-frequency gamma oscillations were observed to synchronize the lateral entorhinal cortex (LEC) and DG while engaging in object learning. Another study published in the same year⁴ reinforced the theory of multiple gamma oscillations, each playing distinct roles. However, this time, the research focused on the visual system—specifically the primary visual cortex (V1) and LGN—rather than the limbic system. These distinct gamma oscillations appear capable of simultaneously carrying different spatial frequency information, demonstrating the phenomenon of multiplexing in the brain. The hypothesis of multiple gamma rhythms could potentially offer future insights into entrainment stimulation (Figure 1). While gamma oscillations may not provide a fundamental cure for Alzheimer's disease, they do appear to help preserve memory function.⁵ Additional research is necessary to identify the optimal target for inducing internal gamma waves that can traverse the entire brain.

Further research addressing the neural mechanisms of 40-Hz entrainment in AD treatment is essential given the multitude of unresolved questions. One significant question is whether various types and processes of AD would benefit equally from the same entrainment method. There is also uncertainty about how different experimental conditions, including the use of varied experimental equipment and light types, could influence the dispute. Furthermore, the potential side effects of 40-Hz stimulation, such as the risk of inducing epilepsy, are still not clearly understood.

In summary, despite the current disagreement surrounding the use of entrainment, efforts to understand the underlying mechanisms continue. Just as new species emerge at the boundaries of diverse ecosystems, novel scientific insights arise at the intersections of various disciplines. We must possess keen discernment to recognize these emerging opportunities and be prepared to persuade others of their potential.

Chuanliang Han: Conceptualization; Funding Acquisition; Writing – original draft; Writing – review & editing.

The author declares no conflicts of interest.